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Evaluating neonatal cord serum metabolome in association with adolescent cardiometabolic risk factors

Pediatric Research (2025)Cite this article

Abstract

Background

Risk factors for cardiometabolic disease may have fetal origins, but the biological pathways linking gestational conditions to these risk factors are only partially understood.

Methods

Among 145 Cincinnati-based HOME Study mother-child dyads, we detected 14,384 cord serum metabolic features using liquid chromatography high-resolution mass spectrometry. We measured cardiometabolic risk factors, including visceral fat, serum triglyceride, high-density lipoprotein cholesterol (HDL), leptin, adiponectin, insulin concentration, glucose, and systolic blood pressure (SBP) at age 12 years. Using sparse Partial Least Squares Regression (sPLS-R), we simultaneously modeled the association of metabolic features with all 8 risk factors. We prioritized features with the highest sPLS-R-derived CM risk factor correlations for metabolic pathway enrichment analysis.

Results

We identified two groups of cardiometabolic risk factors in adolescents maximally associated with neonatal metabolic features. The first was visceral fat, triglycerides, HDL, insulin, and leptin; the second was glucose and SBP. The 178 metabolic features with the highest sPLS-R-derived feature-outcome correlations were enriched in 31 pathways related to short-chain fatty acid, vitamins C and B3, and amino acid metabolism, as well as glycolysis and gluconeogenesis.

Conclusions

We identified 31 pathways that may help elucidate underlying mechanisms between fetal environmental stressors and the development of cardiometabolic risk factors.

Impact

  • Using non-targeted metabolomics, we identified neonatal metabolic features linked to two groups of cardiometabolic risk factors in adolescents, suggesting distinct early-life CM risk trajectories and adolescent subphenotypes.

  • One cardiometabolic group was characterized by higher visceral fat, triglycerides, insulin, leptin, as well as lower HDL; the other group was related to elevated glucose and systolic blood pressure.

  • Using a variable selection and data-dimension reduction technique, these two groups were associated with 178 metabolic features and 31 biological pathways related to short-chain fatty acid, vitamins C and B3, and amino acid metabolism, as well as glycolysis and gluconeogenesis.

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Fig. 1: Correlation structure between eight cardiometabolic risk outcomes measured at age 12 years and 63 cord serum metabolic features in the space spanned by sparse partial least squares-regression: components 1 and 2.
Fig. 2: Heat map and bipartite graph representing pearson correlations between eight cardiometabolic risk outcomes measured at age 12 years and 178 cord serum metabolic features.
Fig. 3: Metabolic pathways significantly enriched for cord serum metabolic features correlated with adolescent cardiometabolic risk.

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Data availability

Data are available upon reasonable request. The HOME Study Principal Investigators welcome new collaborations with other investigators and have actively engaged in collaborative data sharing projects. Interested investigators should visit https://homestudy.research.cchmc.org/contact or contact Drs Joseph M. Braun (joseph_braun_1@brown. edu) and Kimberly Yolton (kimberly.yolton@cchmc.org) to obtain additional information about The HOME Study, discuss collaborative opportunities, and request a project proposal form. The HOME Study Protocol Review Committee reviews proposed research projects to ensure that they do not overlap with extant projects and are an efficient use of scarce resources (eg, biospecimens).

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Funding

This work was supported by National Institute of Environmental Health Sciences grants R01 ES032386, R01 ES025214, P01 ES011261, R01 ES014575, R01 ES020349, R01 ES027224, R01 ES030078 and R01 ES033252.

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Author notes

  1. These authors contributed equally: Elvira S. Fleury, George D. Papandonatos.

Authors and Affiliations

  1. Department of Epidemiology, Brown University, Providence, RI, US

    Elvira S. Fleury, Amber M. Hall & Joseph M. Braun

  2. Department of Biostatistics, Brown University, Providence, RI, US

    George D. Papandonatos

  3. Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, US

    Katherine E. Manz

  4. School of Engineering, Brown University, Providence, RI, US

    Kurt Pennell

  5. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, US

    Aimin Chen

  6. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, US

    Jessie P. Buckley

  7. Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, US

    Kimberly Yolton

  8. Department of Radiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, US

    Kim M. Cecil

  9. Faculty of Health Sciences, Simon Fraser University, Vancouver, BC, Canada

    Bruce P. Lanphear

  10. Department of Family Medicine and Epidemiology, Alpert Medical School, Brown University, Providence, RI, US

    Charles B. Eaton

  11. Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, US

    Douglas I. Walker

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Contributions

G.D.P., E.S.C.F., and J.M.B. conceptualized the study. K.M., K.P., D.W., K.Y., and K.C. acquired the data. G.D.P. and E.S.C.F. analyzed the data. G.D.P., E.S.C.F., and J.M.B. interpreted the data. E.S.C.F. and G.D.P. drafted the article. K.E.M., K.P., A.M.H., A.C., J.P.B., K.Y., K.M.C., B.P.L., C.B.E., D.I.W., and J.M.B. revised it critically for important intellectual content. E.S.C.F., G.D.P., K.E.M., K.P., A.M.H., A.C., J.P.B., K.Y., K.M.C., B.P.L., C.B.E., D.I.W., and J.M.B. approved the final version to be published.

Corresponding author

Correspondence to Joseph M. Braun.

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Competing interests

Joseph Braun was compensated for serving as an expert witness for plaintiffs in litigation related to PFAS-contaminated drinking water.

Consent statement

The Institutional Review Boards (IRBs) of Cincinnati Children’s Hospital Medical Center (CCHMC) and all delivery hospitals approved the study protocol. The Centers for Disease Control and Prevention and Brown University deferred to the CCHMC IRB as the IRB of record. Women provided written informed consent for themselves and their children. Children provided written assent at the age 12 visit.

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Fleury, E.S., Papandonatos, G.D., Manz, K.E. et al. Evaluating neonatal cord serum metabolome in association with adolescent cardiometabolic risk factors. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04322-4

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